Certain types of the human papillomavirus (HPV) are present in the tumor cells of many oral cancers. These viruses are tumorigenic when their transforming proteins are expressed, but we have shown that the cancer cells may lose many aspects of their malignant behavior when they are exposed to antisense nucleic acids of HPV. We will now optimize the use of antisense molecules, with the ultimate aim of developing therapeutic applications. We will screen different sites on the E6 and E7 genes of HPV-18 so as to find the most sensitive regions for inhibition by antisense oligonucleotides. We will measure the effects of hammerhead ribozymes to find if they are more effective than non-ribozyme molecules. We will find an effective method of delivering antisense constructs to oral epithelium, by comparing several virus vectors and promoters. The most effective virus vectors will then be tested in nude mice to find the feasibility of this method of gene therapy for human oral cancer. The project will be developed over a five-year period to the point where human clinical trials of therapy for malignant and premalignant lesions will be possible.